Page 101 - 2020_11-Haematologica-web

CD205 targeting in lymphomas
Combined MEN1309/OBT076 and rituximab showed higher in vivo anti-tumor activity than the single agents
The in vitro synergism with rituximab was validated in vivo using an ABC-DLBCL lymphoma model, OCI-LY-10 (Figure 4). Mice were divided in four groups of ten animals each and were treated with MEN1309/OBT076 (2.5 mg/kg IV, D1 and D12), or rituximab (3 mg/kg IV on D1; 5 mg/kg IV on D12), or MEN1309/OBT076 plus rituximab (same schedule as single agents), or with vehicle only (IV).
Single agents and combinations were more active (P<0.05) than controls (MEN1309/OBT076, rituximab, MEN1309/OBT076 plus rituximab, starting at D10). The combination of MEN1309/OBT076 with rituximab gave significant differences at D17 (P<0.05) versus both single agent arms and tumor eradication. At the used doses, MEN1309/OBT076 presented higher anti-lymphoma activity compared to rituximab, although this was not sta- tistically significant (P=0.06, D17).
Discussion
Here we have shown CD205 expression in hematologic cancers, including lymphomas. Results show that target- ing this antigen with a first-in-class anti-CD205 ADC, MEN1309/OBT076, had both in vitro and in vivo anti-tumor activity in lymphomas. The novel ADC had an anti-tumor activity that was highly correlated with expression of its target CD205 and reached synergism when combined with other targeted agents.
Immunohistochemistry analysis of histological sections of lymphomas, myeloma and leukemia clinical specimens showed that a large percentage of cases (>70%) express CD205. This is in agreement with recently reported data in series of 100 DLBCL and 33 follicular lymphomas in which CD205 positivity was detected in 60% and 79% of the cases, respectively.8 CD205 has also been detected at high expression level in solid tumors (gastric, pancreatic, bladder, breast and colon).7
CD205 is a type I transmembrane glycoprotein and a C- type lectin receptor, which undergoes endocytosis7 and, thus, can be exploited as a novel target for ADC. The fully humanized ADC MEN1309/OBT076 binds to CD205 with high affinity and is rapidly internalized in the cells, delivering the microtubule disruptor DM4 as payload.7 Based on expression pattern in lymphoma clinical speci- mens, we assessed the anti-tumor activity of MEN1309/OBT076 in lymphoma cell lines. The ADC pre- sented a very strong anti-tumor activity with subnanomo- lar IC50 values. Of clinical relevance, at least in cell lines, sensitivity to MEN1309/OBT076 was not affected by DLBCL cell of origin, MYC/BCL2 or TP53 status. The in vitro results were confirmed in a xenograft model using an ABC DLBCL cell line. A single dose of MEN1309/OBT076 at 5 mg/kg led to a complete remission that lasted for at least two months. A second dose was able to obtain a sec- ond remission in the only tumor that presented a regrowth. These data are similar to recent observations in solid tumor models exposed to MEN1309/OBT076.7 The strong in vitro and in vivo data, and the notion that its target
Figure 3. MEN1309/OBT076 combined with the BCL2 inhibitor venetoclax and the anti-CD20 monoclonal antibody rit- uximab exerts cytotoxicity downregulat- ing MCL1, cleaving PARP and upregu- lating CD20 protein. Two cell lines were exposed to MEN1309/OBT076 (1nM), venetoclax (100 nM), rituximab (20 mg/mL) or the combination of the agents for 72 hours. β-tubulin was used as a loading control. Figure is represen- tative of two independent experiments.
haematologica | 2020; 105(11)
2589